Abstract Title

Demyelination in Multiple Sclerosis as an Effect of N-Acetylaspartate Depletion”

Abstract

Multiple sclerosis (MS) is characterized by the demyelination of the central nervous system, which causes progressive neurological disability. Mitochondrial defects in the MS brain, including decreased levels of the neuronal mitochondrial metabolite N-acetylaspartate (NAA), have previously been identified in our lab. We suspect that demyelination in MS is due in part to depletion of NAA through two possible mechanisms. In one mechanism, oligodendrocytes break down NAA into acetate and aspartate which can enter the tricarboxylic acid (TCA) cycle altering oligodendrocyte metabolism. Changes in levels of TCA intermediates have been shown to regulate the activity of histone H3 demethylase enzymes. Preliminary data suggests that neuronal release of NAA enhances myelination by oligodendrocytes through altering trimethylation of histone H3 on lysine 4 (H3K4me3), which regulates genes associated with myelin lipid synthesis. In mechanism two, additional acetyl-CoA resulting from the catabolism of NAA may serve as a substrate for the synthesis of myelin lipids. Here, we will investigate how defects in myelin can be caused by changes in NAA by studying primary cultures of oligodendrocytes and mice that are deficient for NAA (NAT8L-KO). TCA cycle intermediates will be quantitated by mass spectrometry. Western blotting will be used to determine H3K4me3 levels. Quantitative RT-PCR and immunohistochemistry will be used to measure changes in oligodendrocyte differentiation markers. Mass spectrometry, thin layer chromatography, and magnetic resonance imaging (MRI) will be used to measure changes in myelin lipid levels in vivo in the NAA deficient NAT8L-KO mice.

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Mar 11th, 1:00 PMMar 11th, 5:00 PM

Demyelination in Multiple Sclerosis as an Effect of N-Acetylaspartate Depletion”

Multiple sclerosis (MS) is characterized by the demyelination of the central nervous system, which causes progressive neurological disability. Mitochondrial defects in the MS brain, including decreased levels of the neuronal mitochondrial metabolite N-acetylaspartate (NAA), have previously been identified in our lab. We suspect that demyelination in MS is due in part to depletion of NAA through two possible mechanisms. In one mechanism, oligodendrocytes break down NAA into acetate and aspartate which can enter the tricarboxylic acid (TCA) cycle altering oligodendrocyte metabolism. Changes in levels of TCA intermediates have been shown to regulate the activity of histone H3 demethylase enzymes. Preliminary data suggests that neuronal release of NAA enhances myelination by oligodendrocytes through altering trimethylation of histone H3 on lysine 4 (H3K4me3), which regulates genes associated with myelin lipid synthesis. In mechanism two, additional acetyl-CoA resulting from the catabolism of NAA may serve as a substrate for the synthesis of myelin lipids. Here, we will investigate how defects in myelin can be caused by changes in NAA by studying primary cultures of oligodendrocytes and mice that are deficient for NAA (NAT8L-KO). TCA cycle intermediates will be quantitated by mass spectrometry. Western blotting will be used to determine H3K4me3 levels. Quantitative RT-PCR and immunohistochemistry will be used to measure changes in oligodendrocyte differentiation markers. Mass spectrometry, thin layer chromatography, and magnetic resonance imaging (MRI) will be used to measure changes in myelin lipid levels in vivo in the NAA deficient NAT8L-KO mice.